Preparation for diagnosis of the metabolic syndrome and diseases including the syndrome

ABSTRACT

The use of cortisol agonist for preparing a system for diagnosis of the Metabolic Syndrome and related conditions as belly fatness, insulin resistance including increased risk of developing senile diabetes, i.e., diabetes type II, high blood fats and high blood pressure, in which system the dose of cortisol agonist is in an interval where a difference is obtained in the inhibitory effect of the autoproduction of cortisol in individuals suffering from the Metabolic Syndrome, compared to normal values.

This application is the U.S. national stage filing under 35 U.S.C. 371of application PCT/SE96/00708.

BACKGROUND

The metabolic syndrome is characterized by an increased amount ofadipose tissue inside the abdominal cavity (popularly called bellyfatness), insulin resistance with increased risk of developing senilediabetes, i.e. diabetes type II (=NIDDM, non-insulin dependent diabetesmellitus), high levels of blood fats and high blood pressure. Parallelto this is an increased risk of coronary, apoplexy, sudden death andother arteriosclerotic conditions.

A hypothetical explanation to the metabolic syndrome could be anoverproduction of cortisol, a stress hormone which causes anaccumulation of fat inside the abdominal cavity, and insulin resistance.Theoretically this could, through secondary metabolic effects, explainthe other disorders related to the metabolic syndrome.

In Metabolism, vol. 41, No 8, 1992, pages 882-886, it is shown thatbelly fat women have higher secretion of cortisol than “evenly fat”women. The same work describes the effects of acute mental stress on theproduction of cortisol. It was shown that belly fat women, at a givenstress signal, produced more cortisol than ‘evenly fat’ women. Thissuggested, but did not prove, that there may be a relationship betweenstress and belly obesity. A dexamethasone inhibitor test was carried outwith 1 mg dexamethasone and subsequent measurement of cortisol contentin serum. No difference in inhibitory effect on the production ofcortisol could be found between the groups of belly fat women and evenlyfat women and standard values.

Cortisol analogues, e.g. dexamethasone, have for many years been used totrack so called endogenous (often hereditary) depressions in humans. Themechanism behind the test is however so far unknown.

OBJECT OF THE INVENTION AND MOST IMPORTANT CHARACTERISTICS

The object of the present invention is to find a diagnostic test bywhich individuals, running the risk of being affected by one or more ofthe symptoms and/or conditions characteristic to the above describedmetabolic syndrome, can be identified at an early stage. In the presentinvention this is accomplished by a diagnostic system, which as anactive substance has cortisol agonists of a dose in an interval in whicha difference in the inhibitory effect of the autonomous cortisolproduction between individuals with the metabolic syndrome or one ormore of the related risk/conditions and normal values are obtained.Preferably the cortisol agonist is a synthetic cortisol analogues with aglucocorticoidal and/or mineral corticoidal effect, e.g. dexamethasone.The invention also concerns a diagnostic system for the purpose ofdiagnosing the metabolic syndrome, comprising a cortisol agonist of adosage described above, and an agent for measuring the content ofcortisol in saliva or serum.

DESCRIPTION OF DRAWINGS

FIG. 1 shows the hormone signal axis along thecerebrum-hypothalamus-hypophysis-adrenal.

FIG. 2 shows serum cortisol readings after different doses ofdexamethasone given to two groups of individuals, divided according totheir body fat distribution.

DESCRIPTION OF THE INVENTION

The purpose of the invention is the novel medical use of cortisolagonists, which here refers to all synthetic cortisol agonists withglucocorticoidal and/or mineral corticoidal effects. The novel medicalusage is as a diagnostic preparation for diagnosing the metabolicsyndrome and related conditions such as belly fatness, insulinresistance, high blood fat and high blood pressure.

The invention emanates from the hypothesis that during chronic negativestress the hormone signal axis alongcerebrum-hypothalamus-hypophysis-adrenal is strengthened, whichsecondarily likely leads to a down regulation of the GR(glucocorticoidal)—and/or MR (mineral corticoidal)—receptors (cf.Figure). This in turn could lead to a vicious circle where theinhibitory effect of GR and/or MR on CRF (cartocotropin releasingfactor, a signal substance from hypothalamus stimulating the ACTHrelease from hypophysis)—secretion would attenuate. As a result of thisthe cortisol inhibition via the GR− and/or MR receptors would beweakened and thus, every given stress situation would lead to highercortisol secretion (cf. Figure).

In an attempt to test the above hypothesis we have in a scientific studymeasured the basal concentration of cortisol and then givendexamethasone, a synthetic cortisol analogue, that is a synthetichormone substance with the effect of cortisol, at varying dosage. Theidea was that patients having the GR and/or MR receptors down regulatedshould have their cortisol production less inhibited when usingdexamethasbne (an example of a synthetic cortisol analogue) at lowdoses, particularly when compared to the initial value, which often maybe somewhat higher in healthy persons. The inferior inhibitory effect isthus related to the uninhibited cortisol production. When tested onpersons having normal weight, general overweight and on belly fatpersons, we found that the hypothesis agrees with reality. Belly fatnessis fatness inside the abdominal cavity in contrast to general fatness.Those belly fat individuals had also significantly lower basal cortisolvalues at 8.00 o'clock when comparing serum cortisol with the control.Values over or equal to 400 nmol/l were here considered normal values.

The trial group was 22 men between 40 and 60 years. Eight of them werenot fat according to the BMI (body mass index) definition <25 kg/m² and14 were fat with a BMI>25. 12 men had a WHR (waist hip ratio) <1.0 and10 had a WHR>1.0.

Dexamethasone was administered in doses of 0.05, 0.125, 0.25 and 0.5 inan arbitrary order with 1 week intervals.

Dexamethasone was taken at 22.00 o'clock and the cortisol content wasmeasured at 8.00 o'clock on the following morning. To establish theinhibitory effect at least 3 hours and at most 24 hours should passbetween the intake of the cortisol agonist and measurement of thecortisol content.

FIG. 2 shows differences (delta values) between measured cortisolcontent and basal values (not inhibited) after different doses ofdexamethasone. A comparison has been made between men with WHR<1.0 (opensquares) and men with WHR>1.0 (filled squares).

Belly fat individuals were thus shown to have significantly inferiorinhibition by dexamethasone (a synthetic cortisol analogue) at lowdoses. The effect was found at doses between 0.05 and 0.5 mg. Thisshould be compared to the above-mentioned test in which no effect couldbe established at a dose of 1 mg dexamethasone. Thus it has nowsurprisingly been shown that with low doses of dexamethasone asignificantly inferior inhibition of the autoproduction of cortisol bybelly fat individuals is obtained.

For normal weight individuals with and those with general overweight butwithout belly fatness inhibition of the autoproduction of cortisol wasobtained already at a dose of 0.05 mg and continuously up to maximuminhibition at 1 mg (for a few also at 0.5 mg).

For ‘dangerously’ belly fat individuals we found that the inhibitioncould not be measured until the dose was increased to 0.25 mg.Thereafter the maximum inhibitory dose was the same as for healthyindividuals, i.e. maximum inhibition in the interval 0.5-1 mg.

This means that for belly fat individuals the inhibition curve isshifted towards the right. Critical doses which we found significantdifferences in the material (about 20 individuals) are 0.125 mg andparticularly 0.5 mg (most distinct difference with this dose).

For the first time it is also shown that there is a, so-calleddose-response curve, for the dexamethasone test, by which differencescan be detected between individuals at risk of developing the metabolicsyndrome and/or individuals with one or several risk factors/conditionsrelated to the metabolic syndrome, when compared to healthy individuals.

The above mentioned doses hold for the tested substance dexamethasone.The effective dose varies for different cortisol agonists. Crudeconversions of effective doses of the different cortisol agonists arefound in the literature e.g. in FASS.

The cortisol agonist, that in this investigation was dexamethasone, wasadministered as a tablet. The cortisol content was measured twice inserum.

In the same investigation the cortisol content was in parallel measuredin saliva for a small number of individuals. This was done with astandardized quid (Salivette), which the patient keeps in his mouth forabout 45 seconds and thereafter seals in a simple and standardized way.The quids were then analysed for cortisol content. In the test we thenfound a good correlation between the cortisol content in serum and insaliva.

The invention also concerns a diagnostic system comprising a cortisolagonist as described above, and means to measure the cortisol content insaliva or in serum with the aim of measuring the inhibitory effect onthe cortisol production. Such means for measuring the cortisol contentare available as standard devices. The diagnostic system may alsoinvolve means to measure the basal cortisol content since, as shownabove, it has been established that belly fat individuals havesignificantly lower basal cortisol values (less than 400 nmol/l serum)compared to normal population. By measuring at least at two differentdoses of the cortisol agonist (in the case of dexamethasone at 0.125 and0.5 mg), and constructing an inhibitor curve taking into account boththe measured inhibitory effect and the measured basal cortisolconcentration, a very specific diagnostic test is obtained.

What is claimed is:
 1. A method for diagnosing Metabolic Syndrome in anindividual, said method comprising: (a) administering a cortisol agonistto said individual; (b) determining the inhibitory effect of saidcortisol agonist on the production of cortisol by said individualbetween 3 and 24 hours after administering said cortisol agonist; and(c) diagnosing said individual for Metabolic Syndrome based on theinhibitor effect determined.
 2. The method of claim 1, wherein step (b)comprises measuring the cortisol content in said individual.
 3. Themethod of claim 2, wherein the cortisol content in serum or in saliva ismeasured.
 4. The method of claim 1, further comprising measuring thebasal cortisol content prior to administration of the cortisol agonist.5. A method of diagnosing an individual for being at risk of beingaffected by Metabolic Syndrome, said method comprising: (a)administering a cortisol agonist to said individual; (b) determining theinhibitory effect of said cortisol agonist on the production of cortisolby said individual between 3 and 24 hours after administering saidcortisol agonist; and (c) diagnosing said individual for being at riskof being affected by Metabolic Syndrome based on the inhibitory effectdetermined.
 6. The method of claim 1, wherein said cortisol agonist is asynthetic cortisol analogue which has (i) a glucocorticoid effect or(ii) a mineral corticoid effect or (iii) both a glucocorticoid and amineral corticoid effect.
 7. The method of claim 6, wherein the cortisolagonist is dexamethasone.
 8. The method of claim 7, wherein the dose ofdexamethasone is between about 0.05 and about 0.5 mg.
 9. The method ofclaim 8, wherein the dose of dexamethasone is between about 0.125 andabout 0.5 mg.
 10. The method of claim 1, wherein at least two differentdoses of said cortisol agonist are administered at intervals.
 11. Themethod of claim 10, wherein said cortisol agonist is dexamethasone andsaid at least two different doses are 0.125 mg. and 0.5 mg.
 12. Adiagnostic kit comprising: (a) a dosage of a cortisol agonist present inan amount effective for determining a difference in the inhibitoryeffect of the autoproduction of cortisol in an individual having or atrisk of having Metabolic Syndrome or one of its risk factors whencompared with a person not so affected from 3 to 24 hours afteradministration of said agonist; and (b) means for measuring cortisolcontent in a clinical sample from 3 to 24 hours after administration ofsaid agonist.
 13. A method for diagnosing an individual for being atrisk of being affected by at least one of the symptoms of the MetabolicSyndrome, said method comprising: (a) administering a cortisol agonistto said individual; (b) determining the inhibitory effect of saidcortisol agonist on the production of cortisol by said individualbetween 3 and 24 hours after administering said cortisol agonist; and(c) diagnosing said individual for Metabolic Syndrome based on theinhibitor effect determined.